Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the sequence listings and the claims.
The designation xe2x80x9cxcex11dxe2x80x9d is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated xe2x80x9cxcex11axe2x80x9d cloned subtype as outlined in the Pharmacological Reviews (Hieble, et al., 1995). The designation xe2x80x9cxcex11dxe2x80x9d is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated xe2x80x9cxcex11cxe2x80x9d was renamed xe2x80x9cxcex11axe2x80x9d. The new nomenclature is used throughout this application. Stable cell lines expressing these receptors are described herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature (infra). In each case, lowercase letters are used to designate cloned receptors (i.e., xcex11a, xcex11b, xcex11d) and uppercase letters are used to designate pharmacologically defined native receptors (i.e., xcex11A, xcex11B, and xcex11D)
xcex1-Adrenergic receptors (McGrath et al., 1989) are specific neuroreceptor proteins both located in the peripheral and central nervous systems and in tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (a nasal decongestant), and apraclonidine (for treatment of glaucoma). xcex1-Adrenergic drugs can be divided functionally into two distinct classes: agonists (e.g., clonidine and naphazoline), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (e.g., phenoxybenzamine and prazosin), which act to block the effects of norepinephrine. Many of these drugs are effective, but also produce unwanted side effects (e.g., clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years, a more precise understanding of xcex1-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one xcex1-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two xcex1-adrenergic receptor typesxe2x80x94xcex11 and xcex12xe2x80x94existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six xcex1-adrenergic receptors which exist throughout the central and peripheral nervous systems: xcex11A (new nomenclature), xcex11B, xcex11D (new nomenclature), xcex12A, xcex12B and xcex12C (Bylund, D. B., 1992). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current xcex1-adrenergic drugs are not selective for any particular xcex1-adrenergic receptor. Many of these drugs produce untoward side effects that may be attributed to their poor xcex1-adrenergic receptor subtype selectivity.
This invention is directed to compounds which are selective antagonists for cloned human xcex11d receptors. This invention is also related to the use of these compounds as antihypertensive agents (Deng, F. X. et al., 1996). Experimental evidence presented herein indicates that these compounds, while effective at reducing blood pressure in hypertensive individuals, will be devoid of hypotensive actions in normotensive individuals.
This invention is also related to the use of these compounds for the treatment of Raynaud""s disease and for treating bladder instability associated with urinary incontinence (Broten, et al., 1998).
The invention is directed to a method of inhibiting activation of a human xcex11d adrenergic receptor which comprises contacting the receptor with a compound so as to inhibit activation of the receptor, wherein the compound binds to the human xcex11d adrenergic receptor with a binding affinity which is at least ten-fold higher than the binding affinity with which the compound binds to (i) a human xcex11a adrenergic receptor and (ii) a human xcex11b adrenergic receptor, and the compound binds to the human xcex11d adrenergic receptor with a binding affinity which is greater than the binding affinity with which the compound binds to a human 5-HT1a receptor.
This invention is additionally directed to a method of inhibiting activation of a human xcex11d adrenergic receptor which comprises contacting the receptor with a compound so as to inhibit activation of the receptor, wherein the compound has the structure: 
wherein m is an integer from 0 to 2; wherein n is an integer from 0 to 2;
wherein Y is 
wherein Z is 
wherein R1 and R2 (i) are independently H, branched or unbranched C1-C6 alkyl or alkoxy, branched or unbranched C2-C6 alkenyl or alkynyl, branched or unbranched C1-C6 hydroxyalkyl, hydroxy, substituted or unsubstituted aryl or aryl-(C1-C6)-alkyl, or substituted or unsubstituted heteroaryl or heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, hydroxy, branched or unbranched C1-C6 alkyl or alkoxy group, or branched or unbranched C2-C6 alkenyl or alkynyl group; or (ii) taken together form a substituted or unsubstituted cycloalkyl ring containing 3-10 carbons, wherein the substituent if present is a branched or unbranched C1-C6 alkyl group or branched or unbranched C2-C6 alkenyl or alkynyl group;
wherein R3 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R4 is H or CH3;
wherein R5 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R6 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C3-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, C02R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R7 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, aryl, aryl-(C1-C6)-alkyl, CO2R14, CON(R14)2, substituted C1-C6 alkyl, substituted aryl, wherein the substituent is N(R14)2, halogen, OR14 or SR14;
wherein R8 is H or CH3;
wherein R9 is H, F, Cl, Br, branched or unbranched C1-C6 alkyl or alkoxy, CN; wherein R10 is H or F; wherein R11 is H, F, Cl, Br, I, CN, branched or unbranched C1-C6 alkyl or alkoxy; wherein R12 is H, F, Cl, CN, branched or unbranched C1-C6 alkyl or alkoxy; wherein R13 is H or F; wherein X is N or CH; with the proviso that when R11 and R12 are each H, then R9 is F;
and wherein R14 is independently H or branched or unbranched C1-C6 alkyl.
This invention is additionally directed to a compound having the structure: 
wherein n is an integer from 0 to 2; wherein m is an integer from 0 to 2;
wherein Y is 
wherein Z is 
wherein R1 and R2 (i) are independently H, branched or unbranched C1-C6 alkyl or alkoxy, branched or unbranched C2-C6, alkenyl or alkynyl, branched or unbranched C1-C6 hydroxyalkyl, hydroxy, substituted or unsubstituted aryl or aryl-(C1-C6)-alkyl, or substituted or unsubstituted heteroaryl or heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, hydroxy, branched or unbranched C1-C6 alkyl or alkoxy group, or branched or unbranched C2-C6 alkenyl or alkynyl group; or (ii) taken together form a substituted or unsubstituted cycloalkyl ring containing 3-10 carbons, wherein the substituent if present is a branched or unbranched C1-C6 alkyl group or branched or unbranched C2-C6 alkenyl or alkynyl group;
wherein R3 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R4 is H or CH3;
wherein R5 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R6 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2 SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R7 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, aryl, aryl-(C1-C6)-alkyl, CO2R14, CON(R14)2, substituted C1-C6 alkyl, substituted aryl, wherein the substituent is N(R14)2, halogen, OR14 or SR14;
wherein R8 is H or CH3;
wherein R10 is H or F; wherein R11 is H, F, Cl, Br, I, CN, branched or unbranched C1-C6 alkyl or alkoxy; wherein R12 is H, F, Cl, CN, branched or unbranched C2-C6 alkyl or alkoxy; wherein R13 is H or F; wherein X is N or CH; and wherein R14 is independently H or branched or unbranched C1-C6 alkyl.
This invention is additionally directed towards a pharmaceutical composition comprising a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention is additionally directed towards a pharmaceutical composition obtained by combining a therapeutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
This invention is additionally directed towards a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
This invention is additionally directed towards a process of making a compound with structure: 
which comprises reacting a compound with structure: 
with a compound 
to form the compound,
wherein Y is 
wherein Z is 
wherein R1 and R2 (i) are independently H, branched or unbranched C1-C6 alkyl or alkoxy, branched or unbranched C2-C6 alkenyl or alkynyl, branched or unbranched C1-C6 hydroxyalkyl, hydroxy, substituted or unsubstituted aryl or aryl-(C1-C6)-alkyl, or substituted or unsubstituted heteroaryl or heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, hydroxy, branched or unbranched C1-C6 alkyl or alkoxy group, or branched or unbranched C2-C6 alkenyl or alkynyl group; or (ii) taken together form a substituted or unsubstituted cycloalkyl ring containing 3-10 carbons, wherein the substituent if present is a branched or unbranched C1-C6 alkyl group or branched or unbranched C2-C6 alkenyl or alkynyl group;
wherein R3 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R4 is H or CH3;
wherein R5 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
wherein R6 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2 CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2; and wherein R14 is independently H or branched or unbranched C1-C6 alkyl.
This invention is additionally directed towards a method of treating a subject afflicted with a disease which is susceptible to treatment by antagonism of the human xcex11d adrenergic receptor which comprises administering to the subject an amount of the compound of this invention effective to treat the disease.
This invention is additionally directed towards a method of treating a subject afflicted with hypertension which comprises administering to the subject an amount of the compound of this invention effective to treat hypertension.
This invention is directed towards a method of treating a subject afflicted with Raynaud""s disease which comprises administering to the subject an amount of the compound of this invention effective to treat Raynaud""s disease.
This invention is directed towards a method of treating a subject afflicted with urinary incontinence which comprises administering to the subject an amount of the compound of this invention effective to treat urinary incontinence.
This invention is directed towards a method of treating urinary incontinence in a subject which comprises administering to the subject a therapeutically effective amount of a xcex11d antagonist which binds to the human xcex11d adrenergic receptor with a binding affinity which is at least ten-fold higher than the binding affinity with which the xcex11d antagonist binds to (i) a human xcex11a adrenergic receptor and (ii) a human xcex11b adrenergic receptor, and the xcex11d antagonist binds to the human xcex11d adrenergic receptor with a binding affinity which is greater than the binding affinity with which the xcex11d antagonist binds to a human 5-HT1a receptor.